Researchers here examine a proximate cause of age-related dysfunction in a progenitor cell population responsible for tissue maintenance of the endothelium of blood vessels. Declining blood vessel function and integrity is an important part of aging, with many contributing causes, and there is considerable interest in the research community when it comes to identifying ways to restore these losses. As is the case here, however, most researchers focus on possible adjustments to the age-distorted state of cellular metabolism, meaning raising or lowering specific protein levels in order to override cell behavior to some degree, rather than looking to repair the deeper causes of that age-distorted state. I, and others, think that this focus on proximate causes rather than root causes is a poor strategy, doomed to marginal results and slow progress.
Cardiovascular disease (CVD) remains the leading cause of death in the elderly, and treatment is costly. The reduced endothelial function with aging contributes to the development of CVD, so maintaining the normal endothelial integrity is an important therapeutic approach to reduce the age-related risk of CVD. Endothelial progenitor cells (EPCs) are thought to promote postnatal neovascularization and maintain endothelial integrity and function. These cells have aroused the interest of researchers, especially given the limited regenerative capacity of mature endothelial cells. It has been suggested that EPCs not only foster the continuous recovery of the endothelium after injury/damage, but also stimulate angiogenesis.
The function and number of circulating EPCs decreases with aging. Aging impairs the ability of EPCs to regenerate and migrate to damaged blood vessels and ischemic areas to repair the vasculature and promote angiogenesis. Aging EPCs exhibit reduced capacities. Therefore, therapeutic interventions that stimulate EPCs to enhance endothelial repair in elderly individuals have important clinical implications for the aging population. Different mechanisms of EPC senescence have been reported, including telomere shortening, age-related declines in pro-angiogenic factors, increased oxidative stress, reduced nitric oxide (NO) bioavailability and chronic low-grade inflammation. However, the complex molecular network responsible for EPC senescence requires further investigation.
We explored the effects of nuclear factor (erythroid-derived 2)-like 2 (NRF2) on EPC activity during aging. Both in vitro and in vivo, the biological functioning of EPCs decreased with aging. The expression of NRF2 and its target genes also declined with aging, while Nod-like receptor protein 3 (NLRP3) expression increased. Aging was associated with oxidative stress, as evidenced by increased reactive oxygen species and malondialdehyde levels and reduced superoxide dismutase activity. Nrf2 silencing impaired the functioning of EPCs and induced oxidative stress in EPCs from young mice. On the other hand, NRF2 activation in EPCs from aged mice protected these cells against oxidative stress, ameliorated their biological dysfunction and downregulated the NLRP3 inflammasome. These findings suggest NRF2 can prevent the functional damage of EPCs and downregulate the NLRP3 inflammasome through NF-κB signaling.